The IL-2/JAK3/STAT-5 signaling pathway is involved on the initiation and
maintenance of the transcription factor Foxp3 in regulatory T cells (Treg) and
has been associated with demethylation of the intronic Conserved Non Coding
Sequence-2 (CNS2). However, the role of the JAK/STAT pathway in controlling
Foxp3 in the short term has been poorly investigated. Using two different
JAK/STAT pharmacological inhibitors, we observed a detectable loss of Foxp3
after 10 min. of treatment that affected 70% of the cells after one hour.
Using cycloheximide, a general inhibitor of mRNA translation, we determined
that Foxp3, but not CD25, has a high turnover in IL-2 stimulated Treg. This
reduction was correlated with a rapid reduction of Foxp3 mRNA. This loss of
Foxp3 was associated with a loss in STAT-5 binding to the CNS2, which however
remains demethylated. Consequently, Foxp3 expression returns to normal level
upon restoration of basal JAK/STAT signaling in vivo. Reduced expression of
several genes defining Treg identity was also observed upon treatment. Thus,
our results demonstrate that Foxp3 has a rapid turn over in Treg partly
controlled at the transcriptional level by the JAK/STAT pathway